ABSTRACT Alzheimer disease (AD) is the most common cause of dementia and is characterized by extracellular plaques formed by the deposition of amyloid-? (A?) peptide in brain parenchyma and intracellular tangles formed by the aggregation of tau protein. Genetic variations play a large role in AD risk, with the APOE4 allele strongly increasing risk by >3 fold. ApoE4 has been known to promote amyloid development. Importantly, a recent study from Dr. Holtzman's lab showed that apoE4 accelerates tau-mediated neurodegeneration by influencing microglial responses. Microglia are the innate immune cells of the brain, and apoE as well as several other AD risk genes such as TREM2, CLU, and ABCA7 influence their functions. In our efforts addressing AD-related genes on microglial functions, we discovered that TREM2 is a microglial receptor for apoE; linking two critical genetic risk factors for AD in the microglial pathway. However, whether apoE could act in an autocrine fashion on microglia which regulates brain functions, neuroinflammation and AD pathologies in an isoform-dependent manner has not been examined in vivo. Towards addressing this, we have generated conditional mouse models expressing apoE isoforms exclusively in microglia. Our preliminary studies using these mice have shown that apoE4-microglia exhibit impaired responses to injury compared to apoE3-microglia. In addition, our recent microglial translational profiling (RiboTag) or single-cell RNA- sequencing (scRNAseq) studies also identified microglial apoE as a central hub in networks of both amyloid and tau pathology. We hypothesize that apoE expressed in microglia plays critical roles in modulating microglial reactivity and inflammation in an isoform dependent manner with apoE4-microglia contributing to cognitive deficits and increased amyloid and tau pathology. To test our hypothesis, we will use conditional apoE mouse models deleting or expressing apoE isoforms in microglia in the background of wild-type, amyloid, or tau pathology. To address human relevance, we will assess microglial activation states and AD-related pathologies in human postmortem brains from pathologically-confirmed normal, pathological aging and AD cohorts with different APOE genotypes. To uncover cell type-specific pathways modulated by microglial apoE, innovative technologies will be included, such as in vivo microdialysis to measure the brain inflammatory responses at steady-state or in real time upon injury, in vivo 2-photon (2P) imaging to examine the kinetics of microglial mobilization, and scRNAseq to define apoE-regulated, disease-associated gene profiles in microglia and other brain cell types. Together, our study will employ complementary, integrative and systems-based approaches to evaluate the specific roles of microglial apoE isoforms during aging and AD development which should significantly advance our understanding of apoE, microglia, and AD pathogenesis.